This proposal describes a five-year training program for the development of a physician-scientist in the field of Pulmonary and Critical Care Medicine. The principal investigator has completed clinical training and has research experience in the field of pulmonary physiology. The objective of the proposed training program is to provide the skills necessary to integrate the study of cellular mechanisms with whole organ physiologic response. This objective will be achieved through the combination of didactic education and a carefully designed research program mentored by Dr. Robb Glenny, an expert in the field of pulmonary physiology, and Dr. Karol Bomsztyk, and expert in cellular regulatory pathways of gene transcription. The research program will focus on the role of mechanical ventilation as a co-factor in the development of acute lung injury (ALl). Mechanical ventilation strategy determines survival in patients with ALl; however, neither its role in the pathogenesis of ALl nor the cellular pathways involved are known. The proposed experiments will use a rabbit model of sepsis to evaluate both the proximal mechanical stimulus and the end-effector pathway by which mechanical ventilation promotes lung injury. Because TNF-alpha is a principal mediator of inflammation, experiments will look specifically at the major cellular response pathways that result from TNF ligand-receptor binding: NF-kappaB nuclear translocation and initiation of the caspase cascade. Specific aims include: 1) Quantifying the effect of mechanical ventilation on the development of endotoxin-mediated lung injury; 2) Quantifying the effect of different mechanical ventilation strategies on the regional development of endotoxin-mediated lung injury; 3) Evaluating the effect of mechanical ventilation on NF-kappaB activation during endotoxemia 4) Evaluating the effect of mechanical ventilation on caspase-mediated cell death during endotoxemia This application takes advantage of the diversity of resources available within the Department of Medicine at the University of Washington to provide the principal investigator with a unique training program designed to foster a successful research career focused on integrative pulmonary physiology.